ClinVar Miner

Submissions for variant NM_000051.4(ATM):c.2927T>C (p.Val976Ala) (rs146145357)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000166813 SCV000217627 likely benign Hereditary cancer-predisposing syndrome 2018-04-18 criteria provided, single submitter clinical testing In silico models in agreement (benign);Subpopulation frequency in support of benign classification
Invitae RCV000230218 SCV000282916 uncertain significance Ataxia-telangiectasia syndrome 2019-12-31 criteria provided, single submitter clinical testing This sequence change replaces valine with alanine at codon 976 of the ATM protein (p.Val976Ala). The valine residue is moderately conserved and there is a small physicochemical difference between valine and alanine. This variant is present in population databases (rs146145357, ExAC 0.08%). This variant has been reported in an individual affected with breast cancer (PMID: 28503720) and an individual affected with acute myeloid leukemia (PMID: 26689913). ClinVar contains an entry for this variant (Variation ID: 187123). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: (SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). The alanine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx RCV000588819 SCV000293347 uncertain significance not provided 2017-04-26 criteria provided, single submitter clinical testing This variant is denoted ATM c.2927T>C at the cDNA level, p.Val976Ala (V976A) at the protein level, and results in the change of a Valine to an Alanine (GTG>GCG). This variant was detected in a multi-ethnic exome array study; however, no statistically significant association with breast cancer was identified after correcting for multiple comparisons (Haiman 2013). ATM Val976Ala was observed at an allele frequency of 0.08% (8/10,256) in individuals of African ancestry in large population cohorts (Lek 2016). Since Valine and Alanine share similar properties, this is considered a conservative amino acid substitution. ATM Val976Ala occurs at a position that is conserved across species and is located in the beta-adaptin interaction domain (Tavtigian 2009). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether ATM Val976Ala is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000166813 SCV000682090 uncertain significance Hereditary cancer-predisposing syndrome 2019-08-02 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000588819 SCV000694239 uncertain significance not provided 2017-04-13 criteria provided, single submitter clinical testing Variant summary: The ATM c.2927T>C (p.Val976Ala) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 8/120998 control chromosomes, predominantly observed in the African subpopulation at a frequency of 0.00078 (8/10256). This frequency is close to the estimated maximal expected allele frequency of a pathogenic ATM variant (0.0010005), suggesting this variant may be a benign polymorphism found primarily in the populations of African origin. The variant has been reported in the literature, without strong evidence for causality. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Taken together, this variant is classified as VUS.
Counsyl RCV000230218 SCV000799924 uncertain significance Ataxia-telangiectasia syndrome 2018-05-14 criteria provided, single submitter clinical testing
Mendelics RCV000230218 SCV000838513 uncertain significance Ataxia-telangiectasia syndrome 2018-07-02 criteria provided, single submitter clinical testing

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